tbuckley/cabot-search huggingface dataset:
Engineered Treg cells as putative therapeutics against inflammatory diseases and beyond
Authors: Sebastian Bittner, Thomas Hehlgans, Markus Feuerer
Journal: Trends in Immunology (2023)

Regulatory T (Treg) cells ensure tolerance against self-antigens, limit excessive inflammation, and support tissue repair processes. Therefore, Treg cells are currently attractive candidates for the treatment of certain inflammatory diseases, autoimmune disorders, or transplant rejection. Early clinical trials have proved the safety and efficacy of certain Treg cell therapies in inflammatory diseases. We summarize recent advances in engineering Treg cells, including the concept of biosensors for inflammation. We assess Treg cell engineering possibilities for novel functional units, including Treg cell modifications influencing stability, migration, and tissue adaptation. Finally, we outline perspectives of engineered Treg cells going beyond inflammatory diseases by using custom-designed receptors and read-out systems, aiming to use Treg cells as in vivo diagnostic tools and drug delivery vehicles.
Hybrid immunity expands the functional humoral footprint of both mRNA and vector-based SARS-CoV-2 vaccines
Authors: Paulina Kaplonek, Yixiang Deng, Jessica Shih-Lu Lee, Heather J. Zar, Dace Zavadska, Marina Johnson, Douglas A. Lauffenburger, David Goldblatt, Galit Alter
Journal: Cell Reports Medicine (2023)

Despite the successes of current coronavirus disease 2019 (COVID-19) vaccines, waning immunity, the emergence of variants of concern, and breakthrough infections among vaccinees have begun to highlight opportunities to improve vaccine platforms. Real-world vaccine efficacy studies have highlighted the reduced risk of breakthrough infections and diseases among individuals infected and vaccinated, referred to as hybrid immunity. Thus, we sought to define whether hybrid immunity shapes the humoral immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) following Pfizer/BNT162b2, Moderna mRNA-1273, ChadOx1/AZD1222, and Ad26.COV2.S vaccination. Each vaccine exhibits a unique functional humoral profile in vaccination only or hybrid immunity. However, hybrid immunity shows a unique augmentation of S2-domain-specific functional immunity that was poorly induced for the vaccination only. These data highlight the importance of natural infection in breaking the immunodominance away from the evolutionarily unstable S1 domain and potentially affording enhanced cross-variant protection by targeting the more highly conserved S2 domain of SARS-CoV-2.
Neutralization escape of Omicron XBB, BR.2, and BA.2.3.20 subvariants
Authors: Julia N. Faraone, Panke Qu, John P. Evans, Yi-Min Zheng, Claire Carlin, Mirela Anghelina, Patrick Stevens, Soledad Fernandez, Daniel Jones, Gerard Lozanski, Ashish Panchal, Linda J. Saif, Eugene M. Oltz, Richard J. Gumina, Shan-Lu Liu
Journal: Cell Reports Medicine (2023)

New Omicron subvariants continue to emerge throughout the world. In particular, the XBB subvariant, which is a recombinant virus between BA.2.10.1.1 and BA.2.75.3.1.1.1, as well as the BA.2.3.20 and BR.2 subvariants that contain mutations distinct from BA.2 and BA.2.75, are currently increasing in proportion of variants sequenced. Here we show that antibodies induced by 3-dose mRNA booster vaccination as well as BA.1- and BA.4/5-wave infection effectively neutralize BA.2, BR.2, and BA.2.3.20 but have significantly reduced efficiency against XBB. In addition, the BA.2.3.20 subvariant exhibits enhanced infectivity in the lung-derived CaLu-3 cells and in 293T-ACE2 cells. Overall, our results demonstrate that the XBB subvariant is highly neutralization resistant, which highlights the need for continued monitoring of the immune escape and tissue tropism of emerging Omicron subvariants.
A vein bypass first versus a best endovascular treatment first revascularisation strategy for patients with chronic limb threatening ischaemia who required an infra-popliteal, with or without an additional more proximal infra-inguinal revascularisation procedure to restore limb perfusion (BASIL-2): an open-label, randomised, multicentre, phase 3 trial
Authors: Andrew W Bradbury, Catherine A Moakes, Matthew Popplewell, Lewis Meecham, Gareth R Bate, Lisa Kelly, Ian Chetter, Athanasios Diamantopoulos, Arul Ganeshan, Jack Hall, Simon Hobbs, Kim Houlind, Hugh Jarrett, Suzanne Lockyer, Jonas Malmstedt, Jai V Patel, Smitaa Patel, S Tawqeer Rashid, Athanasios Saratzis, Gemma Slinn, D Julian A Scott, Hany Zayed, Jonathan J Deeks
Journal: The Lancet (2023)
Beginner's Guide on the Use of PAML to Detect Positive Selection
Authors: Sandra Álvarez-Carretero, Paschalia Kapli, Ziheng Yang
Journal: Molecular Biology and Evolution (2023)

Abstract The CODEML program in the PAML package has been widely used to analyze protein-coding gene sequences to estimate the synonymous and nonsynonymous rates (dS and dN) and to detect positive Darwinian selection driving protein evolution. For users not familiar with molecular evolutionary analysis, the program is known to have a steep learning curve. Here, we provide a step-by-step protocol to illustrate the commonly used tests available in the program, including the branch models, the site models, and the branch-site models, which can be used to detect positive selection driving adaptive protein evolution affecting particular lineages of the species phylogeny, affecting a subset of amino acid residues in the protein, and affecting a subset of sites along prespecified lineages, respectively. A data set of the myxovirus (Mx) genes from ten mammal and two bird species is used as an example. We discuss a new feature in CODEML that allows users to perform positive selection tests for multiple genes for the same set of taxa, as is common in modern genome-sequencing projects. The PAML package is distributed at https://github.com/abacus-gene/paml under the GNU license, with support provided at its discussion site (https://groups.google.com/g/pamlsoftware). Data files used in this protocol are available at https://github.com/abacus-gene/paml-tutorial.
Geospatial characterization of immune cell distributions and dynamics across the microenvironment in clear cell renal cell carcinoma
Authors: Nicholas H Chakiryan, Youngchul Kim, Anders Berglund, Andrew Chang, Gregory J Kimmel, Ali Hajiran, Jonathan Nguyen, Carlos Moran-Segura, Daryoush Saeed-Vafa, Esther N Katende, Neale Lopez-Blanco, Jad Chahoud, Phillip Rappold, Philippe E Spiess, Michelle Fournier, Daniel Jeong, Liang Wang, Jamie K Teer, Jasreman Dhillon, Fengshen Kuo, Abraham Ari Hakimi, Philipp M Altrock, James J Mulé, Brandon J Manley
Journal: Journal for ImmunoTherapy of Cancer (2023)

Introduction In clear cell renal cell carcinoma (ccRCC), tumor-associated macrophage (TAM) induction of CD8+T cells into a terminally exhausted state has been implicated as a major mechanism of immunotherapy resistance, but a deeper biological understanding is necessary. Methods Primary ccRCC tumor samples were obtained from 97 patients between 2004 and 2018. Multiplex immunofluorescence using lymphoid and myeloid markers was performed in seven regions of interest per patient across three predefined zones, and geospatial analysis was performed using Ripley’s K analysis, a methodology adapted from ecology. Results Clustering of CD163+M2 like TAMs into the stromal compartment at the tumor–stroma interface was associated with worse clinical stage (tumor/CD163+nK(75): stage I/II: 4.4 (IQR −0.5 to 5.1); stage III: 1.4 (IQR −0.3 to 3.5); stage IV: 0.6 (IQR −2.1 to 2.1); p=0.04 between stage I/II and stage IV), and worse overall survival (OS) and cancer-specific survival (CSS) (tumor/CD163+nK(75): median OS–hi=149 months, lo=86 months, false-discovery rate (FDR)-adj. Cox p&lt;0.001; median CSS–hi=174 months, lo=85 months; FDR-adj. Cox p&lt;0.001). An RNA-seq differential gene expression score was developed using this geospatial metric, and was externally validated in multiple independent cohorts of patients with ccRCC including: TCGA KIRC, and the IMmotion151, IMmotion150, and JAVELIN Renal 101 clinical trials. In addition, this CD163+ geospatial pattern was found to be associated with a higher TIM-3+ proportion of CD8+T cells, indicative of terminal exhaustion (tumor-core: 0.07 (IQR 0.04–0.14) vs 0.40 (IQR 0.15–0.66), p=0.05). Conclusions Geospatial clustering of CD163+M2 like TAMs into the stromal compartment at the tumor–stromal interface was associated with poor clinical outcomes and CD8+T cell terminal exhaustion.
Memory profiles distinguish cross-reactive and virus-specific T cell immunity to mpox
Authors: Sarah Adamo, Yu Gao, Takuya Sekine, Akhirunnesa Mily, Jinghua Wu, Elisabet Storgärd, Victor Westergren, Finn Filén, Carl-Johan Treutiger, Johan K. Sandberg, Matti Sällberg, Peter Bergman, Sian Llewellyn-Lacey, Hans-Gustaf Ljunggren, David A. Price, Anna-Mia Ekström, Alessandro Sette, Alba Grifoni, Marcus Buggert
Journal: Cell Host & Microbe (2023)

Mpox represents a persistent health concern with varying disease severity. Reinfections with mpox virus (MPXV) are rare, possibly indicating effective memory responses to MPXV or related poxviruses, notably vaccinia virus (VACV) from smallpox vaccination. We assessed cross-reactive and virus-specific CD4
Liberation of daidzein by gut microbial β-galactosidase suppresses acetaminophen-induced hepatotoxicity in mice
Authors: Yunong Zeng, Rong Wu, Fangzhao Wang, Shan Li, Lei Li, Yanru Li, Ping Qin, Mingyuan Wei, Junhao Yang, Jie Wu, Ali Chen, Guibao Ke, Zhengzheng Yan, Hong Yang, Zhongqing Chen, Zhang Wang, Wei Xiao, Yong Jiang, Xia Chen, Zhenhua Zeng, Xiaoshan Zhao, Peng Chen, Shenhai Gong
Journal: Cell Host & Microbe (2023)

Acetaminophen (APAP) overdose is a leading cause of drug-induced liver injury (DILI). The impact of the gut microbiota and associated metabolites on APAP and liver function remains unclear. We show that APAP disturbance is associated with a distinct gut microbial community, with notable decreases in Lactobacillus vaginalis. Mice receiving L. vaginalis showed resistance to APAP hepatotoxicity due to the liberation of the isoflavone daidzein from the diet by bacterial β-galactosidase. The hepatoprotective effects of L. vaginalis in APAP-exposed germ-free mice were abolished with a β-galactosidase inhibitor. Similarly, β-galactosidase-deficient L. vaginalis produced poorer outcomes in APAP-treated mice than the wild-type strain, but these differences were overcome with daidzein administration. Mechanistically, daidzein prevented ferroptotic death, which was linked to decreased expression of farnesyl diphosphate synthase (Fdps) that activated a key ferroptosis pathway involving AKT-GSK3β-Nrf2. Thus, liberation of daidzein by L. vaginalis β-galactosidase inhibits Fdps-mediated hepatocyte ferroptosis, providing promising therapeutic approaches for DILI.
The RNA editor ADAR2 promotes immune cell trafficking by enhancing endothelial responses to interleukin-6 during sterile inflammation
Authors: Aikaterini Gatsiou, Simon Tual-Chalot, Matteo Napoli, Almudena Ortega-Gomez, Tommy Regen, Rachit Badolia, Valeriana Cesarini, Claudia Garcia-Gonzalez, Raphael Chevre, Giorgia Ciliberti, Carlos Silvestre-Roig, Maurizio Martini, Jedrzej Hoffmann, Rana Hamouche, Joseph R. Visker, Nikolaos Diakos, Astrid Wietelmann, Domenico Alessandro Silvestris, Georgios Georgiopoulos, Ali Moshfegh, Andre Schneider, Wei Chen, Stefan Guenther, Johannes Backs, Shin Kwak, Craig H. Selzman, Kimon Stamatelopoulos, Stefan Rose-John, Christian Trautwein, Ioakim Spyridopoulos, Thomas Braun, Ari Waisman, Angela Gallo, Stavros G. Drakos, Stefanie Dimmeler, Markus Sperandio, Oliver Soehnlein, Konstantinos Stellos
Journal: Immunity (2023)

Immune cell trafficking constitutes a fundamental component of immunological response to tissue injury, but the contribution of intrinsic RNA nucleotide modifications to this response remains elusive. We report that RNA editor ADAR2 exerts a tissue- and stress-specific regulation of endothelial responses to interleukin-6 (IL-6), which tightly controls leukocyte trafficking in IL-6-inflamed and ischemic tissues. Genetic ablation of ADAR2 from vascular endothelial cells diminished myeloid cell rolling and adhesion on vascular walls and reduced immune cell infiltration within ischemic tissues. ADAR2 was required in the endothelium for the expression of the IL-6 receptor subunit, IL-6 signal transducer (IL6ST; gp130), and subsequently, for IL-6 trans-signaling responses. ADAR2-induced adenosine-to-inosine RNA editing suppressed the Drosha-dependent primary microRNA processing, thereby overwriting the default endothelial transcriptional program to safeguard gp130 expression. This work demonstrates a role for ADAR2 epitranscriptional activity as a checkpoint in IL-6 trans-signaling and immune cell trafficking to sites of tissue injury.
Integrative genetic analysis identifies FLVCR1 as a plasma-membrane choline transporter in mammals
Authors: Timothy C. Kenny, Artem Khan, Yeeun Son, Lishu Yue, Søren Heissel, Anurag Sharma, H. Amalia Pasolli, Yuyang Liu, Eric R. Gamazon, Hanan Alwaseem, Richard K. Hite, Kıvanç Birsoy
Journal: Cell Metabolism (2023)
CD4+ T cell-mediated recognition of a conserved cholesterol-dependent cytolysin epitope generates broad antibacterial immunity
Authors: Lisa Ciacchi, Martijn D.B. van de Garde, Kristin Ladell, Carine Farenc, Martien C.M. Poelen, Kelly L. Miners, Carmen Llerena, Hugh H. Reid, Jan Petersen, David A. Price, Jamie Rossjohn, Cécile A.C.M. van Els
Journal: Immunity (2023)

CD4+ T cell-mediated immunity against Streptococcus pneumoniae (pneumococcus) can protect against recurrent bacterial colonization and invasive pneumococcal diseases (IPDs). Although such immune responses are common, the pertinent antigens have remained elusive. We identified an immunodominant CD4+ T cell epitope derived from pneumolysin (Ply), a member of the bacterial cholesterol-dependent cytolysins (CDCs). This epitope was broadly immunogenic as a consequence of presentation by the pervasive human leukocyte antigen (HLA) allotypes DPB1∗02 and DPB1∗04 and recognition via architecturally diverse T cell receptors (TCRs). Moreover, the immunogenicity of Ply427–444 was underpinned by core residues in the conserved undecapeptide region (ECTGLAWEWWR), enabling cross-recognition of heterologous bacterial pathogens expressing CDCs. Molecular studies further showed that HLA-DP4-Ply427–441 was engaged similarly by private and public TCRs. Collectively, these findings reveal the mechanistic determinants of near-global immune focusing on a trans-phyla bacterial epitope, which could inform ancillary strategies to combat various life-threatening infectious diseases, including IPDs.
Chordoma recruits and polarizes tumor-associated macrophages via secreting CCL5 to promote malignant progression
Authors: Jiuhui Xu, Qianyu Shi, Jingbing Lou, Boyang Wang, Wei Wang, Jianfang Niu, Lei Guo, Chenglong Chen, Yiyang Yu, Yi Huang, Wei Guo, Jianqiang Lan, Yu Zhu, Tingting Ren, Xiaodong Tang
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Chordoma is an extremely rare, locally aggressive malignant bone tumor originating from undifferentiated embryonic remnants. There are no effective therapeutic strategies for chordoma. Herein, we aimed to explore cellular interactions within the chordoma immune microenvironment and provide new therapeutic targets. Methods Spectrum flow cytometry and multiplex immunofluorescence (IF) staining were used to investigate the immune microenvironment of chordoma. Cell Counting Kit-8, Edu, clone formation, Transwell, and healing assays were used to validate tumor functions. Flow cytometry and Transwell assays were used to analyze macrophage phenotype and chemotaxis alterations. Immunohistochemistry, IF, western blot, PCR, and ELISA assays were used to analyze molecular expression. An organoid model and a xenograft mouse model were constructed to investigate the efficacy of maraviroc (MVC). Results The chordoma immune microenvironment landscape was characterized, and we observed that chordoma exhibits a typical immune exclusion phenotype. However, macrophages infiltrating the tumor zone were also noted. Through functional assays, we demonstrated that chordoma-secreted CCL5 significantly promoted malignancy progression, macrophage recruitment, and M2 polarization. In turn, M2 macrophages markedly enhanced the proliferation, invasion, and migration viability of chordoma. CCL5 knockdown and MVC (CCL5/CCR5 inhibitor) treatment both significantly inhibited chordoma malignant progression and M2 macrophage polarization. We established chordoma patient-derived organoids, wherein MVC exhibited antitumor effects, especially in patient 4, with robust killing effect. MVC inhibits chordoma growth and lung metastasis in vivo. Conclusions Our study implicates that the CCL5–CCR5 axis plays an important role in the malignant progression of chordoma and the regulation of macrophages, and that the CCL5–CCR5 axis is a potential therapeutic target in chordoma.
Patient demographics, tumor characteristics, and outcomes following surgical treatment of benign and malignant brachial plexus tumors: a systematic review
Authors: Ramin Shekouhi, Harvey Chim
Journal: International Journal of Surgery (2023)

Background: Various treatment options have been introduced for the management of primary tumors of the brachial plexus (BP), ranging from conservative therapy to wide local excision with/without postoperative chemoradiotherapy. However, no consensus exists regarding optimal treatment strategies based on collated and published data. Objective: The aim of this study was to investigate the clinicopathological characteristics and outcome of patients with primary tumors of the BP who underwent surgical treatment. Data sources: A systematic search of the four main online databases, including Web of Science (WOS), PubMed, Scopus, and Google Scholar, was conducted. Study selection: All related articles addressing the clinical outcome and role of surgical interventions for management of primary tumors of the BP. Intervention: Optimal surgical and radiotherapeutic interventions for benign and malignant lesions based on the pathologic characteristics and location of primary BP tumors. Results: A total of 687 patients (693 tumors) with a mean age of 41.7±8.7 years old were evaluated. In total, 629 (90.8%) tumors were benign, and 64 (9.2%) were malignant, with a mean tumor size of 5.4±3.1 cm. The location of the tumor was reported for 639 patients. For these tumors, 444 (69.5%) originated from the supraclavicular region, and 195 (30.5%) were infraclavicular. The trunks were the most common location for tumor involvement, followed by the roots, cords, and terminal branches. Gross total resection was achieved in 432 patients and subtotal resection (STR) was performed in 109 patients. With neurofibromas, STR still resulted in good outcomes. The outcomes following treatment of malignant peripheral nerve sheath tumors were poor regardless of the type of resection. In general, symptoms related to pain and sensory issues resolved rapidly postoperatively. However, the resolution of motor deficits was often incomplete. Local tumor recurrence occurred in 15 (2.2%), patients and distant metastasis was observed in only eight (1.2%) cases. The overall mortality was 21 (3.1%) patients among the study population. Limitations: The main limitation was the lack of level I and II evidence. Conclusions: The ideal management strategy for primary BP tumors is complete surgical resection. However, in some cases, particularly for neurofibromas, STR may be preferable to preserve maximal neurological function. The degree of surgical excision (total or subtotal) mainly depends on the pathological characteristics and primary location of the tumor.
Duloxetine for rehabilitation after total knee arthroplasty: a systematic review and meta-analysis
Authors: Jia-Man Yang, Yi Wang, Jun-Yi Li, Cong-Cong Li, Zhen-Tao Wang, Zhen Shen, Liang Ou, Ze-Hua Chen
Journal: International Journal of Surgery (2023)

The aim was to evaluate the efficacy and safety of duloxetine for postoperative recovery after total knee arthroplasty.The following electronic databases were searched for eligible trials: PubMed, EMBASE, Web of Science, Cochrane Library, VIP, Wanfang Data, and China National Knowledge Infrastructure (CNKI). The search was performed from the inception dates to 10 August 2022. Data extraction and quality assessment were performed by two independent reviewers. Standard mean differences or mean differences with 95% CIs for pooled data were calculated. The primary outcomes were pain, physical function, and analgesic consumption. Secondary outcomes included range of motion (ROM) of the knee, depression, and mental health.This meta-analysis included 11 studies, reporting on a total of 1019 patients. Results of analyses indicated that duloxetine showed a statistically significant reduction in pain at rest at 3 days, 1 week, 2, and 6 weeks and pain on movement at 5 days, 1 week, 2, 4, 6, and 8 weeks. However, there was no statistical significance in pain at rest and on movement at 24 h, 12 weeks, 6 months, and 12 months. Additionally, duloxetine had a significant improvement in physical function, ROM of the knee at 6 weeks, and emotional function (depression and mental health). Moreover, the cumulative opioid consumption at 24 h in the duloxetine groups was lower than in the control groups. But there was no statistical significance for the cumulative opioid consumption over 7 days between the duloxetine groups and controls.In conclusion, duloxetine might reduce pain mainly over a time span of 3 days-8 weeks and lower cumulative opioid consumption within 24 h. In addition, it improved physical function, ROM of the knee with a time span of 1-6 weeks and emotional function (depression and mental health).
High‐Efficiency Antibacterial Hemostatic AgNP@Zeolite/Chitin/Bamboo Composite Sponge for Wound Healing without Heat Injury
Authors: Lu Zheng, Xiaoyun Li, Changliang Xu, Yidi Xu, Yukai Zeng, Manseng Tam, Huan‐Tian Zhang, Xiaoying Wang
Journal: Advanced Healthcare Materials (2023)

Abstract Chitin is a popular hemostatic material, but there are still many deficiencies in its ability to effectively stop bleeding, prevent infection, and fit wounds. Herein, AgNP@zeolite/chitin/bamboo (AgZ‐CB) composite sponges with shape recovery are prepared to minimize blood loss, kill bacteria, and promote wound healing. Notably, the bamboo powder is used for the first time to remarkably enhance the softness of the composite sponge (volumetric expansion ratio &gt;5). The fabricated AgZ‐CB sponge exhibits an excellent killing effect (≈100% bactericidal rate) against both Escherichia coli and Staphylococcus aureus and activates internal and external coagulation pathways to accelerate hemostasis without causing thermal damage (≈5 °C temperature difference). Moreover, the AgZ‐CB sponge shows less blood loss (26 mg) and a shorter time to hemostasis (42 s) than the commercial polyvinyl formal sponge (84 mg and 76 s) in the full‐thickness liver injury model. The in vivo wound healing and biodegradation experiment indicate that AgZ‐CB with excellent biocompatibility can close wounds efficiently. Overall, the AgZ‐CB sponge has great potential in combating a series of obstacles in wound healing.